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Neurotrophic Effects of Decellularized Scaffolds Aid Muscle Regeneration

Review of “Decellularized skeletal muscles display neurotrophic effects in three‐dimensional organotypic cultures” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Decellularized muscles can promote muscle regeneration in volumetric muscle loss models [1], and researchers led by Anna Urciuolo (University College London Great Ormond Street Institute of Child Health, London, UK/Fondazione Città della Speranza, Padova, Italy) recently developed decellularized skeletal muscle scaffolds that retained 3D structural organization of the tissue and extracellular matrix components and growth factors [2]. Notably, these scaffolds could promote tissue regeneration following implantation in an immune-competent murine model of volumetric muscle loss [2]. Interestingly, the authors also observed innervation and regeneration of the neuromuscular junctions, which, alongside similar studies [3-5], suggests that decellularized muscles can trigger the regeneration of the nervous system.

However, whether the neurotrophic properties of the scaffolds or the decellularized muscle itself promoted promote axon invasion remained unclear. Therefore, the Urciuolo team investigated the natural ability of decellularized muscle scaffolds to promote axonal sprouting and invasion in a three-dimensional co-culture system with organotypic spinal cord slides that permits the study of the scaffold’s neurotrophic effect by excluding the influence of other cellular and/or systemic components. Fascinatingly, the results of this new STEM CELLS Translational Medicine study now demonstrate that decellularized scaffolds possess intrinsic neurotrophic properties, thereby supporting their application in muscle regeneration approaches [6].

Raffa et al. began by characterizing the protein composition of decellularized muscles by mass spectrometry, finding the preservation of extracellular matrix structural proteins of both the skeletal muscle and the associated peripheral nerves, including proteins involved in axon growth (collagens, laminins, and fibronectin) and myelin constituents. Furthermore, decellularized muscles also contained extracellular vesicles, proteins involved in extracellular matrix remodeling, and neurotrophic chemokines such as vascular endothelial growth factor and insulin‐like growth factor.

Next, the authors co-cultured the decellularized muscles with spinal cord organotypic sections to investigate the direct neuroattractant effects of decellularized muscles. Excitingly, they discovered the attraction of extending neural axons from the spinal cord to the decellularized muscles and observed the subsequent penetration within the scaffold, thereby suggesting that decellularized scaffolds possess intrinsic neurotrophic properties.

While the authors note the absence of details regarding the mechanisms controlling axon attraction by decellularized muscles, which they hope to delineate during subsequent studies, they hypothesize that such scaffolds could serve as reservoirs of neuroattractant molecules. Overall, the team hopes that their findings will contribute to the development of novel tissue engineering approaches that will promote in vivo reinnervation and functional skeletal muscle regeneration.

For more on how decellularized tissue scaffolds may represent the future of tissue regeneration, stay tuned to the Stem Cells Portal!

References

  1. Urciuolo A and De Coppi P, Decellularized tissue for muscle regeneration. International Journal of Molecular Sciences 2018;19:2392.
  2. Urciuolo A, Urbani L, Perin S, et al., Decellularised skeletal muscles allow functional muscle regeneration by promoting host cell migration. Scientific Reports 2018;8:8398.
  3. Kasukonis B, Kim J, Brown L, et al., Codelivery of Infusion Decellularized Skeletal Muscle with Minced Muscle Autografts Improved Recovery from Volumetric Muscle Loss Injury in a Rat Model. Tissue Engineering Part A 2016;22:1151-1163.
  4. Quarta M, Cromie M, Chacon R, et al., Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss. Nature Communications 2017;8:15613.
  5. Trevisan C, Maghin E, Dedja A, et al., Allogenic tissue-specific decellularized scaffolds promote long-term muscle innervation and functional recovery in a surgical diaphragmatic hernia model. Acta Biomaterialia 2019;89:115-125.
  6. Raffa P, Scattolini V, Gerli MFM, et al., Decellularized skeletal muscles display neurotrophic effects in three-dimensional organotypic cultures. STEM CELLS Translational Medicine 2020;9:1233-1243.